Risk estimates from the Framingham Heart Study indicate that ~75% of essential hypertension in men and 65% of essential hypertension in women is largely attributed to excess body weight and obesity. Convincing evidence from both clinical studies and animal models demonstrates that elevated sympathetic outflow to the kidney and hindlimb vasculature plays a pivotal role in the pathogenesis of obesity-induced hypertension. Despite the important relationship between body weight or adiposity and activation of the sympathetic nervous system, little is known regarding the neural pathways and cellular mechanisms that underlie the sustained increase in sympathetic outflow and arterial blood pressure during obesity. The long term goal of our laboratory is to identify the neural pathways and cellular mechanisms that increase sympathetic outflow and blood pressure in obesity. Two afferent signals to the brain postulated to mediate the elevated sympathetic outflow and blood pressure in obesity are hyperinsulinemia and hyperleptinemia. Our working hypothesis is that diet-induced obesity increases circulating insulin and leptin to activate a descending circuit from the arcuate nucleus to the hypothalamic paraventricular nucleus. Subsequent receptor activation in the hypothalamus increases the discharge of sympathetic neurons in the hypothalamic paraventricular nucleus to enhance excitatory drive to the brainstem and spinal cord. This enhanced excitatory drive increases sympathetic outflow and arterial blood pressure. In this application, we will use state-or-the-art electrophysiological approaches to identify the central mechanisms that support obesity-induced hypertension. Specific aim 1 will identify the cellular mechanisms within the hypothalamic paraventricular nucleus by which hyperinsulinemia and hyperleptinemia increase sympathetic outflow. Specific Aim 2 will identify the cellular mechanisms within the rostral ventrolateral medulla by which hyperinsulinemia and hyperleptinemia increase sympathetic outflow. Specific Aim 3 will identify the mechanisms within the hypothalamic paraventricular nucleus and rostral ventrolateral medulla that support the elevated sympathetic outflow and blood pressure in a rodent model of diet-induced obesity. Our rationale for this project is that identification of the neural pathways and mechanisms that mediate the sympathoexcitatory actions of insulin and leptin, and how these pathways ultimately contribute to obesity-induced hypertension will provide a framework for the development of novel therapeutic treatments. PROJECT NARRATIVE Recent risk estimates indicate that high blood pressure is largely attributed to excess body weight or obesity. This application will identify the mechanisms in the brain that link obesity and hypertension, and therefore provide a framework for the development of novel therapeutic treatments in obese individuals.